ABSTRACT Through bench to bedside translation, we discovered that the PI3K and AR pathways regulate one another in a reciprocal and inhibitory fashion through feedback, explaining the limited efficacy of PI3K pathway inhibitors as monotherapy in clinical trials of patients with metastatic prostate cancer. Based on our work, the first clinical trial of combined PI3K and AR pathway inhibition was recently reported demonstrating a significant benefit for combination therapy in patients with tumors harboring loss of PTEN. Our proposal aims to take these exciting finding back to the pre-clinical space to 1) define biomarkers of intrinsic sensitivity and resistance to inform appropriate patient selection for combination therapy; 2) define the mechanisms of acquired resistance; 3) devise therapeutic strategies to overcome resistance; 4) optimize AR pathway targeting in the setting of PI3K pathway inhibition to maximize tumor response and 5) explore the therapeutic role of FGFR in a novel subset of AR negative prostate cancers.